X-ray crystallographic techniques are being used to study the detailed stereochemistry of enzyme substrates and inhibitors in order to contribute to the analysis of the mechanism of enzyme activity. Studies are proposed to test a hypothesis, suggested from this project, on the mechanism of action of the enzyme aconitase in the Krebs cycle. The importance of the metal ion and the nature and stereochemistry of the inhibition and inactivation of the enzyme, especially by a toxic isomer of fluorocitrate, will be investigated. Similar techniques are being applied to a series of nitrogen and sulphur acridine and anthracene mustards with differing antitumor and/or frameshift mutagenic activities. Attempts to grow crystals of complexes with purines, pyrimidines, and peptides will be made and should lead to information about those factors responsible for the differing biological activity of compounds with very little apparent difference in chemical structure. Some carcinogenic polycyclic aromatic hydrocarbons and their derivatives are also being studied in a similar way. A three-dimensional structure determination of D-xylose ketol- isomerase has been initiated. This study will lead to information on the stereochemistry of the action of an isomerase. In addition, attempts will be made to crystallize and cocrystallize Krebs cycle enzymes.